No one offered me an interview with a geneticist – a person who knows something about DNA. So being such a person myself, I decided to take a look at the decision. And I found errors – starting right smack in the opening paragraph.
“Scientists can extract DNA from cells to isolate specific segments for study. They can also synthetically create exons-only strands of nucleotides known as composite DNA (cDNA). cDNA contains only the exons that occur in DNA, omitting the intervening introns.”
The definition is correct, the terminology, not. “cDNA” does not stand for “composite DNA.” It stands for “complementary DNA.” The document gets it right a little farther on. And I rather like the term “composite DNA,” but it’s confusing to introduce a new term in science when we already have one.
cDNA came into fashion when I was in grad school, circa 1977. Like many genetics terms, it has a very precise meaning, something I pay attention to because I write human genetics books, including 10 editions of a textbook. Changing a term in a textbook takes a lot of thought and feedback.
A cDNA is termed “complementary” because it is complementary in nucleotide base sequence to the messenger RNA (mRNA) that is made from the gene. Enzymes cut from the mRNA the sequences (introns) that do not encode amino acids and retains those (exons) that do encode protein. So a cDNA represents the part of a gene that is actually used to tell the cell to make protein.
A cDNA is created in the laboratory, and it is not a DNA sequence that occurs in nature, although its parts do. Hence, the Supreme Court’s part 2 of the decision, which acknowledges Myriad’s right to use a test based on a complementary, or cDNA.
I did a google search for “composite DNA” and just found the media parroting of today’s decision, and a few old forensics uses with what I think is a different meaning. So a caveat: my conclusion that the term is incorrect and invented is based on negative evidence. If I’m wrong, mea culpa in advance and I will feel like an idiot.
But cDNA isn’t the only questionable term. On page 16, footnote #8 discusses a pseudogene as resulting from “random incorporation of fragments of cDNA.” That’s not the definition I recall or use in my book.
A pseudogene in a classical sense results from a DNA replication error that makes an extra copy of a gene. Over time, one copy mutates itself into a form that can’t do its job. The pseudogene remains in the genome like a ghost of a functional gene. The mutations occur at random because the pseudogene, not being used, isn’t subject to natural selection. The globin gene locus on chromosome 11 is chock full of pseudogenes.
And how is the Supreme Court’s definition of a pseudogene supposed to happen, in nature or otherwise? A cDNA exists in a lab dish. A gene exists in a cell that is part of an organism. How does the cDNA “randomly incorporate” itself inside the cell? Jump in from the dish? Part of the footnote states, “… given pseudogenes’ apparently random origins … ” Pseudogenes’ origins aren’t random at all. They happen in specific genes that tend to have repeats in the sequence, “confusing” the replication enzymes. (See comments for corrections on this. I didn’t know that the viral versions are called pseudogenes too.)
Today’s decision is undoubtedly a wonderful leap forward for patients, their families, and researchers. It is long overdue. And some may think I am nitpicking, not seeing the forest for the trees. But these two questionable terms jumped right out at me — I’d troll for more but I want to post this. What else is wrong? How can we trust the decision if the science is not quite right? And what is the background of the people who research the decisions?
I know nothing about the law, zero, which is why I’m not writing about that. But the science in something as important as a Supreme Court decision should accurately use the language of the field under discussion.]]>
Genome sequencing studies can be boring. It’s not that there are too many of them, although that will surely happen, but sometimes they just don’t tell us anything new. That was the case when last week Medscape asked me to write up a paper in an upcoming New England Journal of Medicine report about sequencing the genomes of uterine fibroids.
I never expected to read “fibroid” and “genome” in the same sentence.
SEQUENCING FIBROID GENOMES
Fibroids are big benign tumors that grow, often in groups like grapes, in the uteruses of about three-quarters of all women. I encountered them personally whilst on the operating table, my obstetrician pulling my middle daughter from my middle, the vertical C-section like bisecting a spaghetti squash.
“Oh my! Here give me some help,” said my doctor to a nurse standing by with a tray. I thought Sarah might have had a twin.
“Ricki, we’ve got some fibroids here. This one’s the size of a baseball!” I hoped she wasn’t talking about my daughter’s head. I suppose I was lucky to get the things out before they made their presence known.
I hadn’t thought about fibroids again until the Medscape assignment. The researchers, from the University of Helsinki, did all sorts of analyses: Whole genome sequencing to spot the point mutations, but also identifying the types of mutations that sequencing misses – copy number variants, indels (insertions and deletions), and rearrangements.
The researchers examined 38 fibroids from 30 women. Two mutations were already known to inhabit fibroid cells – one in an oncogene, one in a tumor suppressor gene. The researchers selected tumors to scrutinize that had either of those, to compare to tumors that didn’t have them.
All of that work ultimately showed that fibroids are very much alike, even in different uteruses. But within one woman, they are clonally connected, like those trees (poplars? I am a botanical dunce) all linked under the ground. The fibroids in a uterus tend to be derived from one leader tumor, and researchers decipher the lineages by aligning genomes from different fibroids according to shared chromosome abnormalities.
On a DNA level, the newly-reported experiments didn’t find much. No mutations in p53, no point mutations other than the two usual suspects, no indels nor large repeats.
But the chromosomal level was a different story. The researchers discovered what looks like the same chromosomal mayhem that is a hallmark of a cancer cell.
I once opened an article in The Scientist with “In cancer, the genome is shot to hell.” For some reason that phrase has been echoed, or perhaps I inadvertently stole it to begin with. The chromosomal chaos of a cancer cell is termed chromothripsis.
It’s like a cytological mega-orgasm, a few chromosomes experience a thundering, one-time explosive event, shattering into smithereens. Then the DNA repair troops come in, only they screw up. If the chromosomes have actually been pulverized, the cell gets routed towards apoptosis (doom) when it reaches the exit point of the cell cycle. But if only a few chromosomes are broken, the DNA repair enzymes try to patch them together. And fail. The result is a chromosomal mess, the brake on its cell cycle forever lifted.
Since chromothripsis had formerly only been known in cancer cells, not the blobbily benign fibroids, the researchers dubbed what they saw “interconnected complex chromosomal rearrangements,” or “CCRs,” which until now meant to me Creedence Clearwater Revival, the cleancut ‘60s band that everyone’s mother loved.
So that’s new, chromothripsis in benign tumor cells. Hopefully this finding will suggest something that can be done to prevent obstetricians from having to tell patients having Cesarean sections that they’ve given birth to baseballs. But at least my baseballs didn’t have hair and teeth in them.
TERATOMAS: THE ‘MONSTER’ MASSES
Last week’s writing about fibroids reminded me of a much more interesting benign growth, a teratoma. Greek for “monster mass,” a teratoma is an outcropping of normal embryonic parts in a person, including representatives of the three layers of the embryo. A teratoma is encapsulated and clearly in the wrong place, such as an ovary.
A teratoma might include hair, teeth, skin, and an occasional bit of gland, a digit, or an eyeball. It usually develops from a wayward sperm or egg that erroneously activated its developmental program, or a somatic cell escaped from an early embryo that didn’t realize it was no longer a part of the whole. Remnants of a twin might also appear to be a teratoma but isn’t quite the same thing.
Teratomas are important in the history of science because their study led to the discovery of human embryonic stem cells (hES), which I chronicled a few years ago in The Scientist and in an essay collection. A quick google just found myself credited with unearthing these facts in a doctoral dissertation.
The stem cell era is usually dated to 1981, when ES cells were derived from mice. That paper has nearly 4,000 citations. But the term “embryonic stem cell” actually first appears in a 1970 paper from a researcher at the Jackson Lab, Leroy Stevens (464 citations), who began isolating the cells from mice with teratomas in the 1950s.
My essay book is called Discovery: Windows On The Life Sciences, published by Blackwell in 2000. Eight people on the planet read it, although a lone review hints that it isn’t as terrible as its Amazon rank might suggest. And Amazon got the title wrong. Anyway, “Discovery” includes one of my favorite descriptions, and because Wiley phagocytized Blackwell and I don’t know who to ask for permission to quote my own work, here it is:
“It is the stuff of talk shows. An 800-pound mass in a woman’s abdomen contains teeth and hair and a jumble of tissue types. A TV program called “The World’s Most Frightening Video” features a man with a second face – an extra nose and mouth that move in unison with his normal ones.
The medical literature offers equally strange reports: a newborn girl with “the underdeveloped lower half of a human body” in her lower back, a young man with a “large greenish mass replacing the left eye” that contains pieces of an embryo’s cartilage, fat, muscle, intestine, and brain.
In another case, an x-ray clearly shows a perfect set of molars embedded in what appears to be a jaw – in a woman’s pelvis. And about a dozen reports describe young men who reached puberty early, then grew the distinctive cell layers of an embryo in their pineal glands, located in their brains! More common are pregnant women who carry not an embryo or fetus, but disorganized masses of specialized tissues, delivering amorphous lumps that sometimes include teeth and hair. Similar growths arise in men, in certain testicular tumors.”
To update my knowledge, I googled teratomas, finding lots of papers from the 1980s, book chapters, and research contract labs that place clients’ hES cells and induced pluripotent stem (iPS) cells into mice. If teratomas form in the rodent’s bellies, then the transplanted cells fulfilled their defining criterion of pluripotency because they give rise to all three tissue layers of the embryo: ectoderm and endoderm sandwiching mesoderm.
How do fibroids and teratomas differ, other than in appearance? It seems that fibroids are fueled by changes in genes, albeit familiar ones, whereas teratomas evolve by changes in gene expression. A fibroid’s genes mutate, and its chromosomes shatter. A teratoma was once a single cell that tried to turn itself into an organized embryo as it divided, only to produce just a tooth or tuft, wrapped in some sort of covering like a California roll.
Both types of growths – fibroids and teratomas — are quite fascinating. They make me wonder anew at how a fertilized egg is able to access its genome, and for all its descendant cells to do so, in a way that forms something as marvelously complex and beautiful as a human body.]]>
8 GENES BEHIND BATTEN DISEASE
Taylor King, of Charlotte, North Carolina, has Batten disease.… Read the rest]]>
Last week’s blog post was about a little girl who had a genetic disease that usually strikes adults. This week’s post is about a teen who has an “infantile” variety of a different neurological genetic disease.
8 GENES BEHIND BATTEN DISEASE
Taylor King, of Charlotte, North Carolina, has Batten disease. Although she was diagnosed at age 8, her genes indicate that she has CLN1, aka ceroid lipofuscinosis, neuronal type 1 – which usually begins in babies.
Unlike Huntington’s disease from last week, which is one distinctive condition with an unmistakable mutation, Batten disease comes in 8 types, corresponding to 8 genes. All 8 forms of Batten disease affect, overall, only 2-4 births per 100,000 in the US, making it a “zebra” rare disease.
The Batten diseases are classic lysosomal storage diseases, in which scant or missing enzymes cause compounds to build up, like cellular garbage collectors going on strike. “Taylor happens to be an anomaly. Most people assume she has juvenile Batten because of her age — she’s almost 15 — but she has infantile, for which the normal life expectancy is around 2-5 years. Taylor produces a small amount of the PPT1 enzyme , linked to the CLN1 gene, so her symptoms didn’t start until later,” explains her sister Laura King Edwards, who started Taylor’s Tale.com to raise funds for Batten disease research.
Children with Batten disease suffer visual loss, seizures, and progressive dementia as their brains drown in a biochemical buildup. I first wrote about it in the circa 2006 version of my human genetics textbook — specifically, Nathan and PJ Milto, from Indiana, who had experimental gene therapy for the “late infantile” form of Batten, aka CLN2. They received gene therapy directly to their brains, which Ron Crystal’s group at Weill Cornell Medical College has been pursuing for many years. When I heard from their father while writing my gene therapy book in 2010, the boys were in their late teens.
Other treatments for Batten disease have been tried. A drug called Cystagon
is being tested at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and an anti-transplant-rejection drug called CellCept is being repurposed in a clinical trial at the University of Rochester.
A trial of neural stem cells taken from human fetuses hit the skids when a 9-year-old girl in the trial died, but her death was attributed to the disease. Another contender that mixes placental stem cells and cord blood is being tried on 16 inborn errors of metabolism at New York Medical College.
Most exciting is the Global Gene Transfer for Batten Disease CLN1 and CLN2 trial being planned at the Gene Therapy Center at the University of North Carolina. Steven Gray will deliver the healing genes into the spinal fluid, an approach that he is pioneering for giant axonal neuropathy, covered here 3 posts ago.
AN UNFORGETTABLE TRIP TO DISNEY WORLD
Gene therapy, drugs new and old, and stem cells are all great approaches. Also effective is a visit to Disney World. And so I turn this week’s post over to Laura King Edwards, reprinted from her blog “Write the Happy Ending”:
“My sister, Taylor, was diagnosed with infantile Batten disease on a blistering summer day in 2006, just 26 days before her eighth birthday. I wasn’t in the room with Mom and Dad when they received the news, but I’ll never forget the geneticist’s words to them:
“Take her home and love her. Make happy memories together. That’s all you can do.”
In the worst hour of our lives, we learned that my bright-eyed, golden-haired, intelligent sister – a second grader who loved to sing and dance and run and play – would go blind, have seizures, and lose the ability to walk, talk, and swallow food. She would deteriorate … confined to a wheelchair. She would have to have a feeding tube. Eventually, she would die – blind, bedridden, and unable to communicate.
For a long time, we refused to condemn Taylor to the horrible fate encoded in her genes. We vowed to fight like hell for my sister – and in the process, for others like her. We never questioned the need to make happy memories with my little sister – we watched the lights of those once-bright eyes fade a little more with each passing month – but we knew that wasn’t ALL we could do.
On December 7, 2006, Taylor, my husband, and my grandparents climbed into my Ford Explorer in our driveway in Charlotte. I loaded a Harry Potter audio book into the CD player and pointed the SUV south for Orlando, FL, where my parents were wrapping up a crash course on lysosomal storage disorders at their first research conference and my sister’s dream of seeing Cinderella’s castle and meeting all of the Disney princesses awaited.
At the end of our 600-mile journey, we pulled into Disney’s Port Orleans Resort and collapsed into our beds. The very next morning, we had breakfast with the princesses inside Epcot Theme Park. Taylor collected all of the royals’ autographs inside a pink and purple autograph book and smiled whenever the princesses hugged her and crouched down to whisper secrets. She marveled at the giant Christmas tree and climbed to the very top of Peter Pan’s tree house.
In the Magic Kingdom, she clapped to the “thump” of the music at the daytime parades and squealed on the peaks and valleys of Space Mountain and Thunder Mountain. She sat on Santa’s lap and asked for reasonable gifts, like new Disney DVDs and pink hula hoops. She called out the colors of the Christmas lights that decorated the floats of the nighttime parade and lifted her face up to the fireworks that painted the sky over Cinderella’s castle.
We packed a lifetime of memories into those two days. We walked the enchanted sidewalks as anonymously as the thousands of other faces there to enjoy their wonders. We made that time ours – and Taylor’s.
Today is “World Wish Day;” it marks the day that the first child received his wish to be a police officer for a day, inspiring the founding of the Make-A-Wish® Foundation. The Make-A-Wish website states that it has fulfilled the wishes of more than 300,000 children with a life-threatening medical condition.
My sister isn’t among them.
I think that Make-A-Wish is an incredible organization and know that they have brought happiness to many children and families. It just wasn’t for us. Perhaps if we’d called the team at Make-A-Wish when we decided to take Taylor to Disney World in 2006, we could have stayed for longer than two days. Maybe we could have dined with Cinderella in her castle instead of the cute Norwegian banquet hall in Epcot. Maybe we could have stayed at the Polynesian instead of the Port Orleans. But while we all knew, deep inside, that we threw the trip together when we did to give Taylor a chance to see Disney while she still could, for those two days, Batten disease was out of our minds – at least as much as was humanly possible. For two days, we were just a family that loved each other, a family on the trip of our lives.
On our second and last night, we stayed in the park long after the last Christmas parade float disappeared around the bend and the last firework sparkled and died over the gleaming turrets of Cinderella’s castle. Just before the park gates closed, we took Taylor back to her favorite ride, Aladdin’s Magic Carpet.
As the attendant invited my sister and me into the circular ride to select our magic carpet, Aladdin and Jasmine appeared at the gate. My sister stopped in her tracks. She stared at the two characters, spellbound. She’d seen them – or other actors in the costumes – numerous times in the parks over the past two days – but this was different. Aladdin and Jasmine were there to ride their magic carpet ride, and we were the only other visitors in sight.
I watched as the two bent down to hug Taylor and invited her to ride with them. My sister could only nod and take Aladdin’s hand as he led her to one of the magic carpet cars. And for the next 10 minutes, the attendant let my sister and me ride that magic carpet with the prince and princess, over and over again, as “A Whole New World” played in the background. When our dream ride came to an end, the valiant prince gave my sister a kiss on the cheek.
If we were to go to Disney World today, my beautiful, sweet sister would not be able to see any of its wonders or walk its paths without a lot of assistance. She’d get tired. We’d have to make frequent medication stops. She might smile for the camera, but she wouldn’t know where to look. She couldn’t sing along to her favorite songs or ask her favorite princesses for autographs.
We still haven’t called Make-A-Wish. But on one enchanted evening, my sister and I rode a magic carpet to the stars. Nothing – including Batten disease – can take that away from us.”]]>
Looking back, signs that Jane Mervar’s husband, Karl, had Huntington’s Disease (HD) started about when their youngest daughter, Karli, began to have trouble paying attention in school. Karl had become abusive, paranoid, and unemployable due to his drunken appearance. The little girl, born in September 1996, was hyperactive and had difficulty following directions. When by age 5 Karli’s left side occasionally stiffened and her movements slowed, Jane began the diagnostic journey that would end with Karli’s diagnosis of HD, which had affected the little girl’s paternal grandmother.
Soon Karli could no longer skip, hop, or jump. And new troubles emerged. ”She had cold sweats, tachycardia, and chronic itching. She fell and suffered chronic pain. By age 6 she was losing her speech and became withdrawn,” Jane recalls. Karli drooled and her speech became unintelligible. By age 7 her weight had plunged, and by 8 she developed pneumonia three times due to difficulty swallowing. By age 9 she required a feeding tube, suffered seizures, and would go long periods without sleep.
AN ADULT’S DISEASE IN A CHILD
This isn’t the way that a disease is supposed to run in families, striking child before parent. HD is regarded as a disease of adulthood, but in fact about 10% of people with the condition are under age 20 – they have juvenile Huntington’s disease (JHD).
“Horse-and-buggy doctor” George Sumner Huntington first described HD in 1872. As a young man he’d accompanied his father and grandfather on house calls in East Hampton, Long Island, where a few local families had a mysterious movement disorder. The youngest Huntington recalled two very thin women gripped by constant contortions, and several men who staggered about as if intoxicated. He later described the symptoms intensifying “until the hapless sufferer is but a quivering wreck of his former self.”
Dr. Huntington deduced the autosomal dominant inheritance pattern of HD. It affects both sexes, with each child of someone with the disease facing a 50:50 chance of sharing the fate. Loss of motor control typically begins in the late thirties, but behavioral and cognitive signs are often present years earlier, sometimes unrecognized. Folksinger Woody Guthrie put a famous face on HD 45 years ago, but the community today needs an Angelina Jolie.
HD symptoms in children differ from those in adults – Karli’s problems in school and stiffness were classic — but inside cells, a similar crisis unfolds in a patient of any age.
The Htt gene encodes the protein huntingtin. The gene normally includes up to 35 copies of the DNA triplet CAG, just before the first exon (protein-encoding part). The disease arises when the gene grows – HD is the quintessential “expanding triplet repeat” disorder. Perhaps the enzymes that replicate DNA as sperm and egg form misalign while duplicating a short repeated sequence, like copying a line in a word document and introducing repeats of a word word word.
The triplet repeat somehow triggers a cascade of destruction, with its most profound effects in the “medium spiny neurons” in the movement centers of the brain. The Htt gene with too many CAGs encodes a protein with too many glutamines. The protein can’t fold properly, sticking to itself and to other proteins, blocking axons in neurons of the brain’s striatum, preventing distribution of essential growth factors. The white matter of the brain shrinks.
Changes in behavior and thinking often precede the constant movements that fascinated the young Dr. Huntington. Irritability, loss of impulse control, and aggression are hallmarks. Jane’s husband Karl spent wildly and threatened his family and others with guns. He spent his final years in a nursing home knowing that social services would take away his daughters otherwise.
AN UNUSUAL MUTATION
Karl was diagnosed six weeks after Karli in 2002. He was 35, she just 6. They died within weeks of each other in early 2010.
But the story gets worse. Karli’s sister Jacey (who founded jhdkids.com), was diagnosed in 2004 at age 13, and her sister Erica in 2007 at age 17. The family history is so complex and unbelievable that even Jane has trouble recalling the chronology. All three girls inheriting the disease is probably just bad luck, but the repeat size for Karli echoes an unusual event.
In HD, gene size matters. Most adults have 40-60 repeats. Karl had 47 and his two older daughters have 47 and 49. But Karli inherited 99 CAGs, a consequence of DNA replication enzymes looping and doubling her father’s 47. It’s little wonder she got sick so fast — longer repeats mean earlier onset.
Most HD kids with very expanded mutations inherit them from their fathers, and this may be due to the different timetables of sperm and egg production. A female at puberty has about 400,000 eggs, each halted on the brink of completing meiosis, when the slippage that expands the gene could happen. But a male shoots out a quarter of a billion sperm with each ejaculation – many chances over a reproductive lifetime for the gene to be miscopied and grow.
WHEN, AND IF, TO TEST
A test to count CAG repeats is essential to confirm a clinical diagnosis of HD. When genetic testing first became available in the mid 1990s, following a decade of using a less-predictive marker test, concern was that people finding out they have the mutation before symptoms begin would freak out. That hasn’t happened. Nor has testing found many takers. Most “at-risk” individuals, those who know they have one affected parent, choose not to be tested.
Because testing raises complicated psychosocial issues, and because onset is usually in the fourth decade, it’s generally not recommended for those under 18. But when the young person has symptoms, it’s a different story.
Martha A. Nance MD, medical director of the Struthers Parkinson’s Center and the director of the HD Center of Excellence at Hennepin County Medical Center, both in Minneapolis, and author of “The Juvenile HD Handbook,” explains the nuances. “It’s important to distinguish diagnostic testing in a child who is having problems from presymptomatic testing in a child whose parent has HD or is at-risk for HD but has no neurologic or psychiatric symptoms.”
Presymptomatic testing doesn’t make much sense, Dr. Nance says. “No treatment hinges on getting an early test result, and the things that people do are probably a good idea whether you have the abnormal gene or not, or at least won’t hurt, such as exercising and eating right.” For children and teens, Dr. Nance says, the psychosocial repercussions of learning test results when there aren’t symptoms can be huge. “The parent who tests his asymptomatic 10-year-old because of guilt, concern, or a desire to plan, removes that child’s freedom to choose. There’s a 90% chance that child, if able to decide for himself, wouldn’t want to be tested.”
Another problem is that it can be very hard to tell when symptoms start, and if they indicate HD or something else. Does a teen who can no longer multi-task at a restaurant job have the family legacy? Is anxiety or irritability due to HD?
The multi-generational nature of the disease complicates matters. “We’re hesitant to diagnose HD in a 13-year-old from a challenging home environment, usually an affected father who probably isn’t working and may have bizarre behavior. The last thing we want to do is take a kid who is profoundly depressed or acting out, whose father is dying of HD, and do a gene test that shows he has a mutation of a size that generally causes symptom onset in a person’s 40s. Then we have just done a predictive test in an unstable 13-year-old,” Dr. Nance explains.
Very few physicians are trained to recognize JHD. Specialists in movement disorders work with older adults, such as those with Parkinson’s disease, and pediatricians rarely encounter HD. “So a child with HD symptoms will either be seen by a pediatric neurologist who knows little about HD, or by an HD neurologist who knows little about kids,” Dr. Nance says.
Diagnosis typically takes 2-7 years as physicians await obvious motor symptoms, or a clear decline in cognitive function. This is too long for families to wait. Dr. Nance and others are working to find better tools to determine when a child’s challenging behavior is just “being a teenager” or some other problem, and when it is due to the onset of HD.
MY CONNECTION TO HD
My family doesn’t have HD, but the disease has woven in and out of my life. Marjorie and Arlo Guthrie encouraged me to pursue science writing after reading a newspaper article I’d written in 1978. It was about my visit to Dr. Michael Conneally’s medical school genetics class at Indiana University, which featured 16-year-old twins with JHD.
Then in 1983, on a muggy May evening, I got a call from Peggy Wallace, who’d taken my human genetics course at Miami University and gone on to do her PhD with Dr. Conneally. His lab was one of four seeking a genetic marker for HD.
Peggy was the first to realize they’d found a marker. Peggy – Dr. Margaret Wallace – went on to post-doc with Francis Collins and then to discover several disease-causing genes, at the University of Florida.
I pitched the HD marker story to popular magazines, but none were interested in such a rare disease. Instead, in those days before the human genome project was even a dream, I wrote about the marker in a wonderful but extinct magazine called High Technology, and in Issues in Science and Technology. I did some preliminary research to write a book about finding the marker, but got little cooperation from the researchers. Alice Wexler, whose mother had HD, eventually did a far better job than I could have.
It took a decade for researchers to finally find the HD gene, a journey complicated by the gene’s location out on the tip of chromosome 4. By 1994 reliable genetic testing for HD became possible for anyone – the older marker test would only work if the indirect DNA sequence could be followed in several family members.
The third chapter in my HD story was Ray. Because of all of the above, when I applied to be a hospice volunteer, I requested an HD patient – something highly unusual, for most hospice patients have cancer.
Ray, then 44, was the last of several siblings who had HD. He’d lived so long with the disease that his worn-out body had ceased the relentless movements. He was eerily still, able to communicate only with his eyes. But the staff at the nursing home, who’d cared for Ray’s older siblings, now gone, and for Ray for 8 years, told me that he loved rock music.
I shared the last four months of Ray’s life, in spring 2005. I communicated with him via a shared iPod, inventing my own music therapy, and wrote a semi-true novel about the experience.
By the end, Ray was skeletal, curled into himself, his organs having shifted in his deformed body in the same way that Jane told me her little girl had become twisted. On the day before Ray died, I wondered why he wouldn’t shut his eyes, as cancer patients do, so I called Dr. Conneally in Indianapolis. He remembered me. “Ricki,” he said quietly, “he won’t close his eyes because he can’t.”
Today I sometimes write for the CHDI Foundation (Cure Huntington’s Disease Initiative), “a global private foundation funding HD science” to the tune of $100 million or so last year. CHDI holds 2-day workshops in which they throw a dozen researchers connected by a general theme – lipid biochemistry, rating scales, stem cells – into a room, and someone like me produces a report summarizing their brainstorming. A CHDI gig is a coveted assignment — always an opportunity to learn.
THE CHALLENGE OF CONQUERING HD
CHDI, HDSA, and others fund an enormous amount of research into developing treatments for HD, from cell biology to population studies that track the disease’s unfolding.
But I’m concerned. The quest that I learned about from Marjorie Guthrie in the 1970s has been going on for too long, the goal too elusive, because the triplet repeat diseases are so unlike other inherited ills. They can’t be fixed by replacing an enzyme or countering a biochemical buildup with diet, or by sending in a normal-length gene, for there’s already one there. The HD mutation is of the nefarious “gain of function” variety. Even refolding the errant protein, as has worked so beautifully in treating cystic fibrosis, hasn’t happened. Silencing the extra CAGs may be the way to go; antisense, RNAi, and zinc finger nuclease approaches may work.
Basic research must keep the drug candidates coming, but support should also focus on the daily challenges that people like Jane Mervar face so gallantly. Jane and her girls have done much for the HD and rare disease communities by sharing their story, which I’ve only touched on here. Even if a gene therapy or repurposed drug or nutritional supplement is never found, there’s still much that health professionals can do to help families with HD. Jane explains how:
“The docs I respect and trust the most are those who can explain what is occurring, and if they cannot help they seek the person who knows the best answer … Teams of specialists helped me keep Karli at home until the end. The last 6 months were the most difficult, meeting her spirit and comfort needs. But she passed on her terms, and I knew we gave it our all.”
May is Huntington’s Disease Awareness month. To help the young people who have this cruel mutation, please contact the University of Iowa HDSA Center of Excellence for Juvenile Huntington’s Disease, where Jane Paulsen, PhD, heads up the JHD effort. One hundred percent of donations fund the research.]]>
Dan Fagin, director of the Science, Health and Environmental Reporting Program at New York University, does a great job in “Toms River” of describing the environmental catastrophe in Toms River, NJ. The book frequently references Jonathan Harr’s, “A Civil Action,” which tells a similar story: over the course of many years, a civil suit finally found in favor of the plaintiffs against three chemical companies whose pollution of the local groundwater in Woburn, MA was linked to childhood cancer.… Read the rest]]>
Dan Fagin, director of the Science, Health and Environmental Reporting Program at New York University, does a great job in “Toms River” of describing the environmental catastrophe in Toms River, NJ. The book frequently references Jonathan Harr’s, “A Civil Action,” which tells a similar story: over the course of many years, a civil suit finally found in favor of the plaintiffs against three chemical companies whose pollution of the local groundwater in Woburn, MA was linked to childhood cancer.
As a PhD industrial chemist of more than 30 years, I’m extremely impressed at how Fagin guides the reader through the complex steps in connecting chemical pollutants to disease. And as a lover of the history of science, I’m pleased that for every new concept in the narrative, Fagin delves into the backstory. A good example: the first demonstrated link to workplace chemical exposure and disease, thanks to Percivall Pott, who in 1775 linked cancer of the scrotum to men who worked as chimney sweeps since childhood. As Fagin points out in several additional examples, diseases of industrial workers are traceable to chemical exposures when doses are high and exposure constant. Woburn provided the precedent for residential exposure.
In addition to weaving the science and history through the story, Fagin adds the faces of the people who lived and died in Toms River. Linda Gillick’s story stands out. Once her son Michael was diagnosed with cancer as a baby, Ms. Gillick led the community in trying to get at the truth of what caused her son’s and other children’s cancers. Her activism is reminiscent of Lori Sames one-woman struggle to bring attention to rare diseases and to raise enough money for a clinical trial for her daughter’s rare condition, giant axonal neuropathy, the subject of last week’s DNA Science blog.
Toms River suffered at least three major environmental insults. The Ciba chemical plant opened there in the 1950s and dumped liquid waste and untreated smoke into the atmosphere for years. The only relief from their assault on the local water supply was when Ciba built a 10-mile long pipe that dumped their waste into the ocean instead of the ground or the Toms River.
Finally, Union Carbide paid the Fernicola brothers, straight from “The Sopranos,” to dispose of their chemical waste. The Fernicolas conveniently found an old egg farm in Toms River, where they dumped thousands of barrels of chemical waste. Not surprisingly, these barrels also leaked into the Toms River and the groundwater that fed the municipal water supply.
Over the years, the tainted groundwater flowed into private wells as the local water supplier delivered it to customers. Time and again, the Toms River Water Company ignored and failed to report organic pollutants in the water system. My one complaint about the book is that Mr. Fagin doesn’t resolve the water company’s knowing delivery of polluted water. Were those who ran the water company ever held accountable?
Part of the complicated tale of Toms River, and of understanding the roots of any environmental disaster, is the use of probability. The author rarely uses the word “proof,” a word frequently misused when describing a chemical mystery like Toms River. In fact, Mr. Fagin again takes us back in history to describe Poisson, who first attempted to describe a disease cluster and whether the cluster was random or non-random. And no description of disease-causation would be complete without discussion of John Snow’s discovery of London’s Broadwick Street pump in 1854 as the source of a terrible cholera outbreak. The Ghost Map, by Steven Johnson, is a riveting account of John Snow’s discovery.
In narrative nonfiction – real-life stories – endings aren’t always neat, and Toms River is no exception.
After years of company and government stalling, studies were finally initiated to see what link, if any, could tie the cancer cases to pollution. Barry Finnett attempted to use a biomarker, hypoxanthine-guanine phosphoribosyl transferase (HPRT), to connect the dots. An exhaustive search found no difference in the level of HPRT in the white blood cells of exposed children versus controls.
Jerry Fagliano’s epidemiology study was the only one that even gave a hint of an association between contaminated water and disease. Fagliano had to parse his data until a connection between drinking water and leukemia in girls emerged, albeit with high levels of uncertainty.
Another interesting story in the book follows the role of Greenpeace and the defense lawyer from a Civil Action, Jan Schlichtman, in negotiating a settlement among many of the parties.
To me, the key to this book is the crushing reality that despite evidence of direct environmental pollution from Ciba, complicity by Union Carbide, and apparent negligence on the part of the local water company, no clear link to human health effects in the community was ever established. What does this mean? Are we not so vulnerable to environmental pollution after all? More likely, the methods needed to connect pollution to human health problems are not yet sophisticated enough to establish association or causation with good statistical certainty.]]>
“When you hear hoof beats, think horses, not zebras.” So goes the mantra of first-year medical students. If a common disease is a horse and a rare disease a zebra, then giant axonal neuropathy (GAN), with only 50 or so recognized cases worldwide, is surely a unicorn.
Five years ago this week, 9-year-old Hannah Sames of Rexford, New York, who lives near me, received a diagnosis of GAN, a disease much like amyotrophic lateral sclerosis. And this month, thanks in part to the herculean fundraising efforts of Hannah’s Hope Fund (HHF), the cover and lead article of the Journal of Clinical Investigation reveal most of the story behind the devastating inherited disease, with repercussions that will reach far beyond the tiny GAN community.
If all goes well at the next Recombinant DNA Advisory Committee meeting at the NIH, a phase 1 clinical trial may be underway before year’s end to evaluate gene therapy for GAN. “A fire started burning deep in my core exactly 5 years ago when Hannah was diagnosed. We will not rest until we have a successful treatment for our kids. They are rare, but they are no longer neglected,” says Lori Sames, Hannah’s mom and executive director of HHF.
On March 5, 2004, when Lori and her husband Matt first glimpsed their newborn daughter’s kinky reddish fuzz, they were both delighted and puzzled. Madison, five, and Reagan, two, have stick-straight hair, as do Lori and Matt. When the birthing goop dried, Hannah’s cap of tight curls sprang to life.
For many months, the little girl seemed okay. She smiled, sat, crawled and hauled herself upright on schedule. But her footsteps were halting, hesitant. Hannah slowly grew clumsy, the strength ebbing from her legs. Lori made the usual rounds of specialists assuring her all was well, but already, filaments of protein were distending the long axons of the motor neurons running down Hannah’s legs, blocking messages to her muscles.
By Hannah’s third birthday, Lori and Matt suspected something was seriously wrong. Both of Hannah’s arches now bowed, and she tottered. More doctors gave false reassurances, hardly hiding their diagnosis of Lori as a helicopter mom. Then Lori’s sister showed cell phone video of Hannah walking to a physical therapist friend, who thought Hannah’s gait was like that of a child with muscular dystrophy. Six months of neurological tests followed, all results normal.
That’s what happens with a disease so rare that few physicians have seen it, or even heard of it. They can’t recognize a unicorn, don’t know what to test for. But finally an astute pediatric neurologist gave Matt and Lori an answer, and it didn’t come from an exome sequence or a sophisticated scan. “He took out a huge textbook and showed us a photo of a skinny little boy with kinky hair, a high forehead, and braces that went just below the knee – he looked exactly like Hannah. And he had GAN,” Lori recalls. Three days of tests at a children’s hospital in New York City confirmed the diagnosis.
Meeting with a genetic counselor was devastating. Lori recites what they learned: “Matt and I are each carriers of GAN, and we passed the disease to Hannah. Each of our two other daughters has a two in three chance of being a carrier. GAN is a rare ‘orphan genetic disorder’ for which there is no cure, no treatment, no clinical trial and no ongoing research.”
“So you are telling us this is a death sentence?” Lori recalls asking the genetic counselor.
The disease would progress slowly, the counselor said. Hannah’s legs would continue to weaken. By first grade she’d likely need a walker in addition to her ankle supports, and soon after, a wheelchair. She might lose her sight and hearing, and eventually be bedridden.
Matt and Lori walked around like zombies for a few days. And then they founded Hannah’s Hope Fund. Their basement became a war room where they used their business backgrounds to assemble the first ever research conference for GAN. As Lori taught herself molecular biology, she became convinced that gene therapy was a logical approach, but at the same time recognized the value of learning anything about GAN. They were lucky to find Jude Samulski, director of the Gene Therapy Center at the University of North Carolina at Chapel Hill, and he recommended a young investigator, Steven Gray, to lead the team. It’ll be the first gene therapy delivered to the spinal cord. A clinical trial is incredibly expensive, and HHF’s fundraising efforts are amazing – they’ve earned $1 million in just the past 8 months. They’re just one of many not-for-profits in the rare disease community who have taken the helm of funding research.
INTO THE INTERMEDIATE FILAMENTS
In parallel to the gene therapy efforts, HHF supports research into the nature of the cellular glitch behind GAN, in the labs of Robert Goldman and Puneet Opal at Northwestern University, Jean-Pierre Julien at Université Laval in Quebec, Pascale Bomont at the INSERM neurological institute in Montpelier, France, and others. The group reports on a remarkable set of experiments in May’s JCI that probe the out-of-control parts of the cell’s inner skeleton, the intermediate filaments (IFs).
GAN is the perfect disease to investigate IFs because it’s caused by a single gene and has a large, measurable effect. Other conditions may affect IFs secondarily, or reflect input from several genes or environmental exposures.
At fault in GAN is a protein called gigaxonin that normally interacts with the IFs. Most kids with GAN have abnormal forms of the protein; Hannah is highly unusual in that she lacks it entirely.
A cell’s inner scaffolding has three types of girders: microtubules made of the protein tubulin, microfilaments made of actin, and the intermediate filaments made of several other types of proteins. The recipes for IFs vary with cell type: keratins in hair, neurofilaments in neurons, and vimentin in fibroblasts, the connective tissue cells that make up much of our bodies. But all IFs share a basic dumbbell shape, with a head, a tail, and a long helix in the middle. The dumbbells align and aggregate into filaments.
BLOCKING CELLULAR TRASH REMOVAL
Being a nerd, when I hear “T and A” I think “tubulin and actin.” And when I hear “UPS” I don’t think of brown delivery trucks spewing package-clutching people – I think of the ubiquitin-proteasome system. The UPS is how cells round up their garbage and get rid of it.
Ubiquitin is a molecule that tags other molecules bound for destruction, like marking rotten produce at a supermarket or the tire of a parked car exceeding the time limit. Other proteins help escort the debris to proteasomes, which resemble spools that tear apart what’s dumped into them, spewing out pieces that are then further degraded.
Gigaxonin – what Hannah’s cells lack – is technically an “E3 ubiquitin ligase adaptor,” based on its DNA sequence. In Hannah’s motor neurons, hair follicles, and probably other places, the utter absence of gigaxonin means the IFs aren’t broken down and recycled. They remain extended and build up, slowly, which is why Hannah was okay for the first two years. I don’t mean this in a bad way, but Hannah is, genetically speaking, like a knockout mouse because she has two deletions of a major part of her gigaxonin genes.
Dr. Goldman and his group looked at fibroblasts from knockout mice and from three patients (called “GAN cells”; not including Hannah’s), tracking the interaction between vimentin and gigaxonin. Their discoveries confirm and extend what’s known about the disease:
• GAN affects IFs, leaving microtubules and microfilaments alone.
• GAN cells don’t overproduce intermediate filaments – the mRNA level for vimentin is normal. Rather, the filaments aren’t broken down on schedule, like garbage collectors going on strike.
• GAN cells are strikingly abnormal. Like a creeping wad of chewed gum, the glommed filaments pervade the cytoplasm, cling to the nucleus in clumps, and capture mitochondria, rendering these energy-extracting organelles swollen and misshapen. The cell’s organelles drown, swept up and suspended in the gunk of a deranged cytoskeleton.
Gigaxonin grabs onto vimentin by the helix part of the barbell. But the researchers were surprised to find that ubiquitin doesn’t enter the picture – gigaxonin must route the IFs to the proteasomes by some alternate pathway. However it happens, the researchers hypothesize, gigaxonin normally dismantles the long IFs into pieces that enzymes further chew up – like splintering a pile of logs into twigs.
GAN’s correctible! At least in a dish. Giving gigaxonin to GAN cells lowered IF levels within 72 hours, which is what gene therapy would ideally do. But kids aren’t collections of cells. If gene therapy goes off target, what could happen? If it works too well, will cells without IFs survive?
ON BEYOND ZEBRA
The research results may suggest new (or perhaps old) drug targets for GAN. Meanwhile, the slow crawl towards clinical trials continues.
In a disturbing twist, Hannah will not be among the first to receive the experimental gene therapy, because she doesn’t make gigaxonin. So if genes placed in her spinal cord enable her motor neurons to make gigaxonin, her body will see a protein it’s never encountered before — a red flag to the immune system. And so before Hannah can join the clinical trial that has not yet begun, she must have treatments to accustom her immune system to gigaxonin. That means suppressing T cells or a stem cell transplant from one of her sisters.
This week at the American Society of Gene and Cell Therapy annual meeting in Salt Lake City, researchers are brainstorming ways to modulate the immune system to accept a protein introduced with gene therapy, with Hannah the case study. “How can they safely treat her? What is the best way to suppress her immunity? And how will they determine when it’s safe to wean her?” Lori asks. She’s there, of course.
The GAN extended family that Lori and Matt Sames brought together five years ago lost their first member March 26, beautiful and inspiring 21-year-old Casey Davies Ketcham. Blogged Lori at the time, “Today, I feel very angry, sad, agitated … Angry we were all given GAN… Angry this has taken so long to bring to a Phase 1 trial… Rest in peace Casey. With God’s continued grace we will conquer GAN. We will feel your strength and peace when our kids receive gene delivery. You wanted to be the first, and you will be there in your vibrant spirit.”
Casey’s legacy is also that what researchers learn about GAN will likely help many others. “IF aggregates form in several types of neurological disorders in addition to GAN—such as ALS and Parkinson’s disease,” says Dr. Goldman. Add to that variants of spinal muscular atrophy and Charcot-Marie-Tooth disease, Alexander disease, Lewy body dementia, and Alzheimer’s disease. ”Our results suggest new pathways for disease intervention. Finding a chemical component that can clear the aggregations and restore the normal distribution of intermediate filaments could one day lead to a therapeutic agent for many neurological disorders,” says lead author Saleemulla Mahammad, a postdoctoral researcher at Northwestern.
I hope the days when rare diseases were considered “orphans,” and ignored, are finally gone, as more and more families form not-for-profit organizations that push research far beyond what was once possible. What we learn about the unicorns and zebras can often help the horses too.
(Hannah’s story is told in chapters 10 and 11 of my book The Forever Fix: Gene Therapy And The Boy Who Saved It.)]]>
What Erin received, a few days later, was a shock.… Read the rest]]>
When 23-year-old Glamour magazine editor Erin Zammett Ruddy went for a routine physical in November 2001, she expected reassurance that her healthy lifestyle had been keeping her well. After all, she felt great.
What Erin received, a few days later, was a shock. Instead of having 4,000 to 10,000 white blood cells per milliliter of blood, she had more than 10 times that number – many of the cells cancerous. Erin had chronic myeloid leukemia (CML). Two years before her diagnosis, CML was a death sentence. But the drug Gleevec saved her and many others. It offers perhaps the best example of translational medicine.
A LIFE TURNED UPSIDE DOWN BY CANCER
“I had just returned from a nice, long lunch to find a message from my doctor. Could I call back? Something had come up in my blood work,” Erin told me in 2007, when I met her at her office in midtown Manhattan.
I’d read Erin’s blog and invited her to tell her story in my human genetics textbook, which she did, with a photo of her grimacing during one of her many bone marrow samplings. And what a success story it’s been!
Next week Erin celebrates the start of her 11th year with the cancer essentially gone, thanks to Gleevec. Also next week the story of the drug, The Philadelphia Chromosome by fellow PLOS blogger Jessica Wapner, will be published. At the same time panoramic yet detailed, the new book chronicles the researchers and molecules behind Gleevec, beautifully complementing Erin’s 2005 book “My So-Called (Normal) Life.”
When Erin was diagnosed, Glamour had just published a story about the new drug, which the FDA had approved in May 2001. Erin contacted the physician heading the 3-center clinical trial, Brian Druker, MD, director of the Knight Cancer Institute at the Oregon Health & Science University and Howard Hughes Medical Institute Investigator. She flew to Portland for tests, and soon began taking one pill of Gleevec every day. After a short bout of stomach cramps and a little eye puffiness, she, like nearly everyone to receive the drug, responded.
Over a few weeks, Erin’s cancer ebbed away — and stayed away, even with brief hiatuses for two pregnancies. She announced her third last week.
Before Erin’s story, my textbook had covered the discoveries that led up to Gleevec, because they are a classic in genetics. I’d thought the story would make a terrific book, but couldn’t see how I could tell such a complicated and technical tale. Now Jessica Wapner has done exactly that, in her masterpiece “The Philadelphia Chromosome.”
BRAIDING THE RESEARCH THREADS
Gleevec arose from an unexpected assembly of pieces that no one initially realized went to the same puzzle. First came the discovery of an unusual “minute” (small) chromosome in 1960, in two men with CML whose cells wound up in the lab of pathologist Peter Nowell at the University of Pennsylvania, where PhD student in cytogenetics David Hungerford, from the nearby Fox Chase Cancer Center, worked. Nowell and Hungerford’s telltale “Philadelphia chromosome” – Ph1 — showed up in other CML patients too. Dr. Nowell tells the story in the Journal of Clinical Investigation.
It wasn’t until 1972 that Janet Rowley at the University of Chicago, using new, higher resolution chromosome stains and famously spreading out her images on her kitchen table, discovered that the Philadelphia chromosome is a translocation – one chromosome 9 and one chromosome 22 swap parts (chromosomes are numbered by size, 1 the largest).
By 1984, with generic chromosome staining having evolved into the DNA-sequence-specific “FISH,” (fluorescence in situ hybridization) researchers zeroed in on the two genes juxtaposed in the translocation: the Abelson oncogene (abl) from #9, and the breakpoint cluster region (bcr) from #22.
The two genes, cut and rejoined, generate two unusual chromosomes. The larger, #9 with a bit of #22, has no known effect; the other, tiny #22 with a smidgeon of #9, called the bcr-abl fusion gene, drives certain white blood cells to divide like crazy, becoming leukemia.
The cancer isn’t inherited; it just happens, for cancer is a genetic alteration of somatic cells. “The only difference between normal cells and CML cells was that in the former, bcr and abl were separate and that in the latter, bcr and abl were fused. And that fusion turned the once harmless abl into an oncogene,” Wapner writes.
The BCR-ABL oncoprotein that the bcr-abl fusion gene encodes was already very familiar to drug developers – it’s a tyrosine kinase, a member of a family of enzymes that oversee signal transduction pathways. But pharma had been focusing on cancers more common than CML.
If the pharmaceutical industry learned anything from this saga, it was that curing the rare can lead to curing the common. And the BCR-ABL oncoprotein was the key to halting Erin’s cancer, CML. The drug-to-be was first called CGP-57148B while at Ciba-Geigy and largely ignored, then STI-571 when Ciba-Geigy and Sandoz merged to beget Novartis. After clinical trials and lightning-speed FDA approval – 10 weeks — STI-571 became Gleevec in the US, soon Glivec elsewhere.
HOW GLEEVEC WORKS
The drug fits into a pocket of the BCR-ABL oncoprotein, displacing the energy molecule ATP. This prevents the jettisoning of a lone phosphate that starts the bucket-brigade-like passing that sends signals inside the cell. A tyrosine kinase is an enzyme that adds a phosphate to a tyrosine amino acid on a particular protein. When ATP binds the abnormal oncoprotein, continuous cell division results. Slapping on Gleevec is a little like shutting up a blabbermouth.
Preclinical experiments took years – in rodents, beagles, rabbits, monkeys, and most tellingly, the bone marrow cells of CML patients, where the drug worked. In people the intravenous infusion that the company pushed was ineffective, but the pills that some of the researchers and Dr. Druker favored did work – as a far less invasive daily orange pill. And that wasn’t the only unusual thing – compared to standard chemo, Gleevec has no side effects, other than transient eye puffiness, cramps, and bone pain as the cancer cells die off.
Gleevec is the first drug to combat cancer at its source, rather than targeting cancer cells by their excess antigens, the way that the breast cancer drug Herceptin works. And the clinical trial results for Gleevec were astonishing. I remember reading the abstract in the April 5, 2001 New England Journal of Medicine many times, in utter disbelief. Of 54 patients, 53 responded to the drug.
As Gleevec did its job, three measures of success were clear. Numbers plummeted: leukemic cells, Philadelphia chromosomes, and copies of the messenger RNA representing the fusion gene. The speed of FDA’s evaluation and approval of the submitted data set a record that still holds. “The Philadelphia chromosome” opens with one patient’s experience as this happened, and the book includes the names and contributions of the many individuals who made Gleevec a reality.
Wapner flawlessly weaves the three threads of Gleevec’s beginnings into a tightly knit fabric: how viruses subvert normal cell division genes into killer oncogenes, the development of kinase inhibitors, and the Philadelphia chromosome tale. The success was most stunning in the sickest patients. She writes:
“The responses began within a week after starting STI-571. Among several dying patients, white blood cell counts dropped, making room for restorative red blood cells to proliferate and heal the body. The color returned to their faces. They gained strength. They got up and out of their wheelchairs and walked out of the hospital.”
Wapner also captures Dr. Druker’s realization that what he’d predicted had actually happened, as the first patients brought back from the brink of death tearfully thanked him. “I realized they were so far ahead of me. They already accepted that this drug had worked and had changed their lives,” Dr. Druker said.
Gleevec was 41 years in the making, from 1960, when two young medical researchers in Philadelphia noted an unusual tiny chromosome that their leukemia patients shared, to FDA approval in 2001. Writes Wapner, with hindsight, “The story of how the Philadelphia chromosome led to CML was like a hundred painters applying brushes to a canvas at some time or another over twenty-five years, driven only by curiosity and, sometimes, a vague hope that their work might eventually be relevant to human cancer. There’d been no final picture in mind and no awareness that they were even painting something together. And yet there it was. A scientific masterpiece.”
On May 17, Peter Nowell, Janet Rowley, and Brian Druker will share the
Albany Medical Center Prize in Medicine and Biomedical Research for their work on Gleevec. “Their collective achievements opened new fields of cancer research and have improved the lives of many,” said Joseph R. Testa, Ph.D., co-director of the Cancer Biology Program at the Fox Chase Cancer Center. Dr. Hungerford died in 1993, at age 66, of lung cancer.
The Gleevec story didn’t end with Erin’s rare cancer, CML. Gleevec is currently approved in the U.S. to treat 10 cancers, and has been tweaked so that patients whose cells become resistant can continue to benefit. And Druker has developed other drugs for when resistance persists, always staying one step ahead of the cancer.
More than fifteen kinase inhibitors have been FDA-approved, treating different cancers, with 500 more in clinical trials at half that many companies. Gleevec led the way.
“This type of targeted therapy is the future of cancer drug therapy and the future is here,” said Druker on learning of the Albany prize. “With the technology we have available today, what took 40 years — the discovery of the Philadelphia chromosome to the approval of Gleevec — can happen in a matter of months. It’s an exciting time to work in this field.”
THE PHILADELPHIA CANCER STORY: THE SEQUEL
A small molecule like Gleevec is only one new way to combat cancer. A completely different type of cancer treatment based on an engineered immune system molecule is unfolding, again in Philadelphia, right now. Novartis, sponsor of Gleevec, has given $20 million to build a facility for “chimeric antigen receptor,” or CAR, technology, on the Penn campus. CAR technology is in clinical trials to treat several cancers and HIV infection.
A chimeric antigen receptor is part T cell receptor, part antibody segment, its mosaic gene delivered aboard lentivirus (disabled HIV) to T cells. The CAR leads the T cells to the cancer cells distinguished by their many copies of the corresponding antigen. Zelig Eshhar, at the Weizmann Institute of Science, originated the general idea of retooling T cell receptors in the 1980s .
CAR technology was pioneered on patients with acute lymphoblastic leukemia (ALL), which affects 70,000 people in the U.S.. The New York Times chronicled the recovery of 6-year-old Emma Whitehead. Bruce Levine, one of the inventors of CAR technology with Carl June and others, told me all about Emma and the other patients now in complete remission, at a recent gene therapy conference – which I’ll cover in a future blog.
Let’s celebrate the translation of knowledge of the basic life sciences — cell biology, biochemistry, genetics, and immunology — into saving lives.]]>
SUNY Stony Brook, Fall semester, 1973. 500+ wannabe doctors pack into the lecture hall, squinting as a small figure up front slaps down overheads, scribbling CHNOPS atoms and various dots and dashes, changing the acetate sheets faster than any human brain can register them.… Read the rest]]>
SUNY Stony Brook, Fall semester, 1973. 500+ wannabe doctors pack into the lecture hall, squinting as a small figure up front slaps down overheads, scribbling CHNOPS atoms and various dots and dashes, changing the acetate sheets faster than any human brain can register them. Each night after a lecture, like fatty acids emanating from the glycerol backbone of a triglyceride, we’d align in the library to copy the incomprehensible overheads at 3 Xerox machines.
Stony Brook University, Fall Semester, 2012. The professor, wearing a remote microphone and holding an iPad, walks about the cavernous lecture hall, as the students, in groups, work problems, helped by a troop of last year’s students. The entire event is available online for those who can’t make it to class.
Recently I received an e-mail from the new chairperson of chemistry at Stony Brook, Nicole Sampson, describing organic chemistry as “a bad memory for those pursuing the dream of entering a health profession.” I read on. “Fortunately, this situation has changed at Stony Brook. Professor Frank Fowler has been applying advances in the cognitive sciences, in combination with new technologies, to teach students how to take a complex set of data and use it to solve problems.”
So I e-mailed professor Fowler, who’d taught my husband’s organic lab. Larry, as a chem major, had small classes where professors actually talked to students. I was among the great horde of pre-meds.
“Sure, I’d love to talk to anyone who’ll listen. The old days were not the good days,” Fowler answered to my first e-mail.
CULLED FROM THE HERD
If it weren’t for organic chemistry, I’d be an MD.
I knew by the first chemistry test freshman year 1972 that my childhood dream of becoming a doctor was over. By the end of my third semester of chemistry – the first of organic – I’d earned my third “D,” and was henceforth known as the D orbital. (By a statistical fluke, I got a C for the fourth semester. It happens.) I did, however, earn A’s in the lab, so I was not a complete moron.
I hadn’t yet taken biochemistry, so didn’t think anything that flew past in organic was of any relevance to medicine. At the risk of inducing an anxiety attack, I just unearthed Morrison and Boyd, the classic textbook (who knew I’d grow up to write those things myself?), to see if I’d have a flashback. And I did.
I looked up Friedel-Crafts alkylation, a phrase hovering in my distant memory, and soon discovered that this is the addition of a carbon-containing group to a benzene ring. According to the textbook, “In Friedel-Crafts alkylation, the electrophile is typically a carbonium ion. It, too, is formed in an acid-base equilibrium, this time in the Lewis sense,” followed by several reactions.
“What has this to do with setting a bone, removing a spleen, delivering a baby, or treating cancer?” I bellowed to my husband.
“The human body is a giant chemistry set that’s making and breaking covalent bonds,” he answered, obviously brainwashed. So I asked the same of the good Dr. Fowler.
“If anything, a molecular knowledge is more important for physicians and people going into health care now than it ever was. My dermatologist said, ‘I never use organic!’ But skin cancer is a perfect example of photochemistry of the skin,” Fowler said.
A NEW ORGANIC
“So what’s changed?” I asked Fowler on the phone.
“We understand better how students learn, and it’s not when you talk at them. They learn by doing.”
The 1100 students in his two classes use the “inverted classroom” paradigm that is sweeping education and is working well in teaching genetics – students learn the material on their own time (hence delaying the extinction of textbook authors like me), then work in groups to solve problems during class.
“Work in groups? In organic?” I blurted, astonished.
“A group without a lot of smart people can get the right answer more frequently than just a smart person. This is very important in solving problems in the future,” Fowler said, insisting that today’s students are different. They eagerly work together, free of the anger and competitive streak that pervaded my own class, when everyone did anything to get the highest grades possible, lest they fail at the lofty goal of getting into med school. I even saw one student, whose name I still remember, spit into someone’s flask in lab, to better his own grade.
But I don’t think even a group of Einsteins could have helped me, because I just couldn’t see molecules in three dimensions. It’s inborn. Today, I can’t follow a dance instructor who faces the class – my brain can’t flip the perspective.
I thought that being able to rotate molecules on a laptop would have helped me, seeing the active site come into view as its substrate approaches, like this molecule of the drug Gleevec nestling into its target kinase (subject of next week’s blog). But Dr. Fowler still relies on handheld, tinker-toy like molecular models. “Life is 3D. You won’t understand problems in medicine if you don’t understand that a lot of molecules look alike because of their shape.”
He timidly brings up the gender factor. Do boy toys, like tools and model kits, better prepare kids to see molecular interactions in three dimensions, compared to Barbies? I think it’s a case-by-case thing. I grew up with model kits and war toys, and all I ever did with dolls was rip their heads off.
I might have benefited from Powerpoint presentations, though, which bridge the overheads of my time with modern animations too fluid to follow. “With Powerpoint you only see stuff come in and disappear. You can take a single topic, maybe 8 slides worth, and no student can tell when I go from one to the next. I can tell a much smoother story,“ Dr. Fowler says. He also uses “clickers” so that students can provide real-time feedback on whether or not a concept is penetrating.
A NEW WAY TO RECRUIT MED STUDENTS
The day after I spoke with Dr. Fowler, a Perspective by David Muller, from Mt. Sinai ‘s Icahn School of Medicine, appeared in the New England Journal of Medicine, describing a new way to prepare students for medical school that absolves them from much of the misery of organic chemistry.
The pre-med mantra of science courses, Muller wrote, was “used to cull the herd of talented aspiring physicians.” Sociologist Donald A. Barr from Stanford University and colleagues from there and UC Berkeley also point out in “Chemistry courses as the turning point for premedical students“ that students from under-represented minority groups have a particularly difficult time staying on the path to a career in medicine, a problem largely attributed to chemistry courses.
Since 1987, Mount Sinai has encouraged humanities majors to apply to the medical school. Those accepted can learn “clinically relevant” parts of organic chemistry and physics in an 8-week summer session, and no Medical College Admissions Test, the MCAT. The Humanities and Medicine Program (HuMed) did so well in preparing future doctors that it’s evolved into FlexMed, which encourages students of all majors to pursue medicine at Mt. Sinai.
Half of each new medical school class at Mt. Sinai will consist of these more broadly-trained individuals. The school will recruit students as sophomores and “assure” them of acceptance by summer, junior year. As undergrads they’ll take two semesters each of biology, chemistry, any science lab, and one semester of physics, statistics, ethics, and health policy (or global health or public health). Proficiency in Spanish or Mandarin is strongly encouraged.
A person can now become a physician yet avoid the year of organic chemistry with lab. Ditto the MCAT. (My favorite sentence about reliance on MCAT scores: they “effectively exclude bright, creative, motivated students who aren’t strong test takers.” Me.) But I imagine selection will be challenging. “We will use many of the same metrics we use in our other selection models: evidence of excellence in research, community service, clinical exposure, athletics or the arts, clinical experiences, evidence of leadership ability, etc. We will also look to grades and SAT or ACT scores for some general sense of academic competence, but they won’t be the deciding factor,” Dr. Muller wrote in an e-mail.
If I weren’t out to pasture since being culled from the herd, I’d sign up.
THE “HEALTH HALO” OF ORGANIC FOODS
Organically-grown, soon shortened to simply organic, foods became popular shortly after my traumatic encounter with organic chemistry. At first I wondered how a food could NOT be organic, NOT contain carbon. But of course the designation refers to freedom from pesticides, as if manure doesn’t contain carbon.
According to the dictionary, “organic” means “derived from living matter” or
“compounds containing carbon.” But the meaning has morphed into “natural,” “good,” or “better than that chemical-drenched crap.” The word that still gives me palpitations and makes me think of ketones and aldehydes has come to be nearly synonymous with “healthy,” and people will readily pay three times what the regular stuff costs, for that illusion of superiority.
Researchers at Cornell University’s Food and Brand Lab recently described a “health halo effect” that refers to consumers’ perception of superior taste, appearance, fewer calories, and overall value to any food bearing the flag “organic.” They asked 115 folks in an Ithaca, NY mall to compare organic versus regular versions of yogurt, cookies, and potato chips. The pairs were, of course, identical, the perceptions not. Anything labeled organic was deemed healthier, tastier, and even less caloric. Perhaps the investigators should have compared, say, carrots instead of prepared foods.
I survived my three D’s in organic chemistry. Occasionally I still have a nightmare of being in that lecture hall, trying and failing to fathom anything, re-living the desperation of knowing my score on an exam would equal the number of answers I got right by chance. My husband has helped by taking the same approach as allergy treatments, desensitizing me with a tee-shirt bearing the citric acid cycle. In the end, I found the clear logic of the relationship among three types of molecules much more comforting than the mysterious named reactions of organic chemistry: DNA, RNA, and protein.]]>
I “met” Emmanuel in 2007, when he e-mailed me after finding my contact info at the end of my human genetics textbook, which he was using in his senior year of high school. He is my personal link between DNA Day and World Malaria Day. But the dual commemoration also reminds me of the classic study that revealed, for the first time, how hidden genes can protect us – that carriers of sickle cell disease do not get severe malaria.
The goal of the DNA Science blog is “genetics in context,” and what better time to do that than today, by linking genetics to infectious disease. (Also see A GPS View of the Human Genome from two weeks ago.)
OUR AFRICAN SON
Emmanuel’s charm and intelligence came through easily in his e-mails and Facebook posts, and soon, my husband and daughters began to correspond with him too. He called us Mom and Dad, calling himself “Your Son.” This made me uneasy at first – I didn’t want to insult his mother – but Eman assured us that this is the way in Africa. When my husband had a hernia operation unnoticed by the rest of the world because Michael Jackson and Farrah Fawcett died that day, Eman somehow found a phone and called, worried.
It’s very expensive to mail anything to Liberia, and most stuff that makes it is stolen. Eman sent us traditional clothing through a friend traveling here. I sent Obama tee-shirts, which miraculously arrived, and Eman proudly gave them to his siblings. President Obama is much loved in this country founded by American slaves.
Eman wrote often that he wanted to fight the infectious diseases that plague his nation, as he did in this letter to a geneticist colleague of mine seeking sponsorship:
“I am Emmanuel, age 21. After my studies in biology, I wish to become a medical doctor. In a country of 3.5m people and a little over 200 medical doctors (mostly foreign) there remains a great distance between health workers and healthy people. Most doctors live and work in urban areas, leaving those in rural areas vulnerable to diseases and little or no health care. Every day in Liberia, people die of curable diseases and that is very devastating. I have decided to pursue studies in Medicine to help change this situation. I hope that one day I will be of help to Liberia and the world. I want to become a doctor of the people, mostly based in the rural area where people rarely get access to health care.”
We encouraged and supported Eman, and he was almost through his second year of med school in mid-March, when he sent this e-mail:
Dear Mom and Dad,
I was admitted at a local hospital yesterday after I fell off. According to the nurse, onlookers took me to the hospital. I do not know what happened. I will get to know once the Doctor gets to see me tomorrow.”
I asked what he fell off of, and this turned out to be one of several linguistic misunderstandings we’ve had. “I mean I fainted. Loss of consciousness and postural tone,” he answered, already sounding like a doctor.
Two days passed, and then we got an e-mail from Eman’s brother that he’d been readmitted, with stage 3+ malaria. I didn’t know what that meant.
“3+ means it is severe. That could even lead to madness. His blood is very low maybe due to the typhoid. We hope he gets better for school soonest,” wrote Eman’s brother. Parasite-stuffed red blood cells were obstructing small blood vessels in his brain, causing his unconsciousness. If he didn’t die, I read, he’d probably be okay. Since then, our African son has been on a roller-coaster ride of chills and fever, trying to get back to school.
I try to imagine what’s happening in his body. The life cycle for malaria is complicated. An Anopheles mosquito delivers protozoa (Plasmodium species) with its bite, and the parasites settle in the liver. Then they head to the red blood cells, where they persist in asexual forms (while fever and chills ensue). Some of them burst out, forming sex cells that are sucked up by another mosquito, which then injects the infectious cargo into another person.
Despite the decrease in annual malaria deaths by a third over the past two decades, the disease remains the #1 cause of morbidity and mortality in Liberia, where live expectancy is 59. In Africa, a child dies of malaria every 60 seconds.
Knowing the genome sequences of all the players in malaria – the vector, the parasite, and the host – are important in better understanding the disease. But when I think about malaria today, on this dual DNA/Malaria day, I cringe at some uses of DNA testing.
Here in the U.S., people are getting their exomes sequenced to know what conditions they might develop decades hence, while a world away, people still die in days from the types of infectious diseases that Eman has battled. Two years ago he had cholera, malaria, and amoebic dysentery all at once. Meanwhile, Americans send their spit to genetic testing companies that reveal such vital information as eye color, whether cilantro tastes like soap, or whether they sneeze in bright sunlight.
THE CLASSIC SICKLE CELL/MALARIA PAPER
The worlds of DNA and malaria collided back in 1953, the year that Watson and Crick published their famous paper on DNA’s structure.
Anthony Allison, a British doctor with a degree in biochemistry and genetics from Oxford, grew up at the epicenter of human evolution, in the Great Rift Valley in Kenya. As a young man he met Louis Leakey, at the Olduvai Gorge in Tanzania. Steeped in the central idea underlying evolution — that diversity drives it — Allison set out to investigate how the one inherited trait that could be easily followed back then varied among tribes: blood types. In 1949, right before he left on the research trip that would lead to his string of papers in 1954, a colleague wondered aloud about the high incidence of sickle cell disease. Inherited conditions that kill early in life tend to be extremely rare — only carriers and new mutations sustain it.
Intrigued, Allison surveyed the incidence of sickle cell disease among members of 35 tribes in East Africa. And it was staggeringly high – up to 40% — but only in areas where malaria was endemic.
The mutation rate for the beta globin gene would have to be extraordinarily high to keep it so common. Was there another explanation? Could carriers have a health advantage that enables them to survive to reproduce, passing on the mutation?
When Dr. Allison looked at maps of the distribution of both diseases, the connection jumped out at him. Where malaria was most prevalent, so too was sickle cell disease. When he counted the numbers of malaria parasites in the red blood cells of carriers versus non-carriers, like Eman, the puzzle pieces assembled.
Dr. Allison concluded that “persons with the sickle-cell trait have a considerable natural resistance to infection with Plasmodium falciparum,” in Transactions of the Royal Society of Tropical Medicine and Hygiene.
A name for this dual disease phenomenon already existed, coined by Dr. Allison’s mentor at Oxford, E. B. Ford: balanced polymorphism. A heterozygote (carrier, with two different alleles of a gene) has a survival advantage over either homozygote (2 identical alleles). People with 2 copies of the mutant hemoglobin allele (hemoglobin S) die young of sickle cell disease, but those with 2 copies of the healthy allele (hemoglobin A), if bitten by a disease-carrying mosquito, contract and likely succumb to malaria.
The idea was striking, but not entirely novel. In 1948, J.B.S. Haldane had noted a relationship between another disease of beta globin, beta thalassemia, and malaria – but he didn’t connect the dots, as Dr. Allison did.
Once the malaria-sickle cell connection emerged, looking back at history explained malaria’s stronghold in Africa — and raises fears today about the effects of global warming in creating mosquito habitats.
Around 1000 B.C.E., Malayo-Polynesian sailors from southeast Asia traveled in canoes to East Africa, introducing wonderful new crops – coconuts, yams, bananas, and taros. Clearing the jungle to cultivate these newcomers provided breeding grounds for mosquitoes.
A cycle set in. Settlements with many sickle cell carriers – people who escaped both diseases – were able to clear more land to grow food. The mosquitoes, and their stowaways, flourished. This rapid changing of allele frequencies is the most profound illustration of evolution that I know.
But we still don’t know exactly how sickle cell carriers are protected against malaria. Asexual parasites soak up oxygen from the hemoglobin inside red blood cells, shriveling some of a carrier’s red blood cells into their characteristic crescent shapes. The cells are shunted to the spleen, slated for destruction along with their parasite stowaways. If carriers do get malaria, it’s mild. But other mechanisms may be at play too.
I don’t know if Dr. Allison is still around, but if he is, I hope a reader will send him this blog. He told Economist writer Laura Spinney in 2009, “Every generation likes to rediscover me.” We should celebrate his contribution today. It’s every bit as important as the DNA discovery.
OTHER DISEASE PAIRS
Sickle cell disease and malaria remain the “textbook example” of balanced polymorphism, but others are equally intriguing:
• Cystic fibrosis protects against certain diarrheal diseases because intestinal lining cells of carriers have fewer intact chloride channels, keeping bacteria or their toxins out.
• Phenylketonuria (PKU) persists because pregnant women who are carriers don’t lose their fetuses to ochratoxin, a poison made by fungi on rotting vegetables. People ate tainted vegetables during times of famine, which is why the world’s highest prevalence of PKU is in Ireland.
• Prions are infectious proteins that lie behind mad cow disease and related conditions. People who are heterozygotes for the prion protein gene make prion protein that can’t twist into the infectious form. In the mid-1990s, the several people in the UK who developed the human form of mad cow disease were all homozygotes, with two identical copies of the gene. Again, carrier status protects.
Another example of carrier advantage is just an hypothesis, and I don’t know who originated it. Several of the dozen-and-a-half “Jewish genetic diseases” affect the brain – terrible conditions such as Tay-Sachs, Canavan, Alzheimer, Niemann-Pick, and Batten diseases. Their prevalence reflects the serial shrinking of the Jewish gene pool in the wake of purges such as pogroms and the holocaust, so that distant cousins inadvertently marry distant cousins, unknowingly joining mutant genes in small children who suffer from these brain diseases. But maybe balanced polymorphism is favoring their carrier relatives. What might be their advantage?
Might quick-witted ghetto occupants or prisoners been more likely to escape, keeping the mutations in the gene pool? If a good sense of humor is a surrogate for intelligence, then a second line of evidence might be the overrepresentation of Jewish people among comedians. Call it the Seinfeld effect.
DISCOVERING THE HUMAN PROTECTOME
How many other protective carrier states are hiding in our genomes? We have the computational tools to find them, but it’s difficult to detect omissions. Researchers must identify which diseases the carriers of the same single-gene conditions never get. That’s negative evidence, but it’s how we can unveil our “protectome.” We’ve been following these diseases for decades. The data await mining.
And it all started with the work of Anthony Allison, on malaria and sickle cell disease – the joining of genetic and infectious disease that we mark today.]]>
From now until DNA Day, April 25, bloggers will be worshipping the human genome. Nature.com will offer podcasts (PastCasts) and last week, Eric Green, director of the National Human Genome Research Institute, spoke to reporters, summarizing the “quantitative advances since the human genome project.”
It’s also the 20th anniversary of my textbook, Human Genetics: Concepts and Applications. Writing the 10 editions has given me a panoramic view of the birth of genomics perhaps different from those of researchers, physicians, and journalists.… Read the rest]]>
From now until DNA Day, April 25, bloggers will be worshipping the human genome. Nature.com will offer podcasts (PastCasts) and last week, Eric Green, director of the National Human Genome Research Institute, spoke to reporters, summarizing the “quantitative advances since the human genome project.”
It’s also the 20th anniversary of my textbook, Human Genetics: Concepts and Applications. Writing the 10 editions has given me a panoramic view of the birth of genomics perhaps different from those of researchers, physicians, and journalists. Here are a few observations on the evolution of genetics to genomics, as I begin the next edition.
A LONG AND WINDING ROAD
My textbook almost didn’t happen. Back in 1980, when I pitched it to the acquisitions editors descending on the zoology department at Miami University, no one cared.
“Human genetics? How about intro bio? Not enough sales in genetics.”
In 1992, the year my intro text was finally published, I found myself next to my favorite editor at a dinner. Human genetics had recently edged onto the editorial radar, thanks to media attention to the fledgling human genome project. I scribbled a table of contents on a dinner napkin, which served as a makeshift contract, and soon the project was a go. But the publisher still thought of genetics as an obscure outpost of academia, so the editors left me pretty much on my own.
I’m a storyteller, and so from the beginning, the textbook featured true tales from families with genetic diseases: A mom whose 5-year-old died from missing part of chromosome 5; a young man with XXY syndrome; and a 16-year-old wondering why visitors at an exhibit on spina bifida at a local science museum voted that people with this condition, which he has, should never have been born. Including the voices of real people added so much humanity to the textbook – the competitors tended to feature white male scientists – that one critic accused me of “writing like a woman.”
When I wrote the first edition, I couldn’t have imagined that the exome – a term not yet invented – would one day be sequenced from DNA in a spit sample, and sent, for $99, to an also-not-yet-invented web-based company. And according to the NHGRI, sequencing a human genome, which initially took 6-8 years and about a billion dollars, now can be done in a day or two for $3,000-$5,000.
GENETICS HEADLINES 20 YEARS AGO
What else was happening, and hadn’t yet happened, in human genetics when I wrote the first edition, circa 1992?
• The Huntington’s disease mutation had just, finally, been discovered, after a decade-long “chromosome walk” from a marker out on the tip of chromosome 4.
• Gene therapy basked in the afterglow of the first clinical trial, to treat an immune deficiency; 18-year-old Jesse Gelsinger hadn’t yet died from gene therapy for a urea cycle disorder, which derailed the field. The first FDA approval for gene therapy in the US may come this year, marking another “3” year in the history of genetics.
• The Human Genome Project, public consortium version, was getting underway, but the Celera Genomics team didn’t exist, as such.
• The first genome of a free-living organism had yet to be sequenced – that would happen two years later.
• The film GATTACA was four years away from dramatizing a society crippled by misuse of genetic information.
A look at Nature Genetics from September 1993 reveals the state of genetics.
The lead editorial probed the now infamous paper by Dean Hamer from the National Cancer Institute introducing what would become known as the gay gene on the X chromosome, ushering in the era of genetic determinism. Other articles mapped genes for infertility, migraine, and an assortment of rarities. A study about a baby with “leprechaunism” caught my eye – it’s been deemed offensive since then and is now called Donohue syndrome. That will probably soon become something about an insulin receptor gene mutation, following the trend to get away from eponyms.
Over the editions, the number of genes fell by an order of magnitude, from 200,000 to about 20,300 today. Other things increased. Today we recognize more types of RNA, species of Australopithecus, cancer-causing genes, sequenced genomes (humans and others), and genome regions that don’t encode protein.
PAST EXCEPTIONS ARE TODAY’S NEW RULES
As genetics has become genomics, the focus has shifted from the traditional study of diseases and mutants towards normal function and inherited variation.
Some chapters grew so large with all that added normalcy that they split, like giant amoebae redistributing their biomass into two individuals. “Multifactorial Traits” spun off “Behavior,” and “DNA Action” (the trek from DNA to RNA to protein) begat “Gene Expression.”
I’ve long wondered what to do with Gregor Mendel. Pea plant experiments may seem archaic, but I apply the laws they revealed whenever I counsel a couple about their chances of having a child with a single-gene disease. Yet responses to my Scientific American blog on what the heck to do with Mendel argued for minimizing him.
The problem isn’t the stretch from peas to humans – it’s more that the either-or simplicity of Mendel’s laws isn’t very helpful in the clinic, where individual genes do not operate as autonomously as a pea plant with wrinkled or smooth seeds.
In my textbook, the seeming exceptions to Mendel’s laws grew from a tacked on mention in edition #1, to an entire chapter (““Exceptions and Extensions to Mendel’s Laws”) in edition #2, to a renaming by edition #8, circa 2008, to “Beyond Mendel’s Laws,” recognizing that the exceptions had become the rules.
The oddities no longer considered odd are the forces that alter how we experience single-gene traits and illnesses, such as the environment (epigenetics) and other genes. These factors explain why some people with disease-causing mutation combinations don’t get the disease (“incomplete penetrance”) and why some mutations cause differing degrees of illness in different individuals (“variable expressivity”). Complicating diagnosis is “genetic heterogeneity,” when mutations in more than one gene cause a disease or trait, and “phenocopy,” when an environmentally-caused condition resembles an inherited one.
ALLELIC DISEASES – WE STILL DON’T UNDERSTAND SINGLE GENES
Edition #10 (2011) introduced yet another complexity lurking in simple Mendelian genetics — allelic diseases. That’s when different mutations in the same gene cause different diseases, depending upon the gene part and body part affected.
I started thinking about allelic diseases before they had a name. Once the cystic fibrosis (CF) gene was discovered in 1989 and researchers identified hundreds of mutations, clinical variations could be detected. Most people have the classic lung and pancreas symptoms, but some people only have frequent sinus infections or bronchitis, and men may have only infertility. These manifestations are all considered to be CF. Yet different mutations in the beta globin gene had been known for decades, and the diseases that they cause considered to be separate clinical entities, such as sickle cell disease, methemoglobinemia, and beta thalassemia. Why weren’t the distinctive guises of CF considered separate illnesses, too?
By the time I was writing the 10th edition, allelic diseases had started to accumulate, and they grew more and more intriguing. One mutation in a gene greatly elevates risk for Alzheimer disease, yet another variant of the same gene causes severe acne. The gene that causes Menkes disease, with its trademark ultra-kinky hair, lies behind peripheral neuropathy too. Marfan syndrome can also be stiff skin syndrome. The inborn error Gaucher disease (glucocerebrosidase deficiency) shares a gene with Parkinson’s disease.
The list of allelic diseases is growing. Finding the underlying commonalities among these peculiar pairs of illnesses may reveal shared mechanisms and potential drug targets. But the subtler lesson is that while the news is full of sequencing genomes, we haven’t yet figured out all the relationships among the variants of well-studied genes.
Perhaps the most astonishing evolution has been in genetic testing; it starts every edition of my textbook.
Edition #1 opened with the story of how a mother’s astute observation that her children’s pee smelled weird led to development of the diet to prevent symptoms of phenylketonuria (PKU). It’s still one of the best single-gene stories because it has a happy ending.
Editions #2 and 3, from 1997, looked ahead a few years to fetal testing that was just becoming widely used. Edition #4, from 2001, introduced college students Mackenzie and Laurel, named for soap opera characters. In each subsequent edition, they took a changing menu of genetic tests, laying the groundwork for the genetic testing that exploded from the clinic to spit-in-a-tube direct-to-consumer testing in 2008.
I invented Laurel and Mackenzie, although the tests they took in the first pages of each edition existed. Gradually descriptions of the first real sequenced human genomes began to appear, but I put them in the final chapter, on genomics. Edition #9 featured the first three genomes, from Craig Venter, James Watson, and “YH,” a Chinese man. Said Dr. Venter at the 2008 annual meeting of the American Society of Human Genetics of his and Dr. Watson’s genome results: “You probably wouldn’t suspect this based on our appearance — we are both bald, white scientists.”
The current edition ends with the genome of Stephen Quake , a pioneer of high-throughput DNA sequencing and one of the first to talk about his genome. In the 3 years since I wrote that, articles and books discussing someone’s genome seem to appear on a weekly basis.
What will I do for edition #11? By the time it’s published, genome sequencing will certainly be available for under $1,000, and will be well on its way to becoming part of standard health care. It’s hard to believe that in just 20 years, coverage of human genome sequencing in my book grew from a brief boxed reading, to part of a chapter on gene mapping, to its own chapter.
But now, as I embark on edition #11, I might shrink or drop the “human genome” chapter altogether, for it has now become a lens through which we must view every other aspect of the science we once called genetics.]]>